Lipid kinases catalyse the phosphorylation of lipids to produce species involved in the regulation of a wide range of physiological processes, including cellular migration and adhesion. The PI3-kinases are membrane associated proteins and belong to the class of enzymes which catalyse the phosphorylation of lipids which are themselves associated with cell membranes. The PI3-kinase delta isozyme (PI3 kinase δ) is one of four isoforms of type I PI3 kinases responsible for generating various 3′-phosphorylated phosphoinositides, that mediate cellular signalling and has been implicated in inflammation, growth factor signalling, malignant transformation and immunity [See Review by Rameh, L. E. and Cantley, L. C. J. Biol. Chem., 1999, 274:8347-8350].
The involvement of PI3 kinases in controlling inflammation has been confirmed in several models using pan-PI3 kinase inhibitors, such as LY-294002 and wortmannin [Ito, K. et al., J Pharmacol. Exp. Ther., 2007, 321:1-8]. Recent studies have been conducted using either selective PI3 kinase inhibitors or in knock-out mice lacking a specific enzyme isoform. These studies have demonstrated the role of pathways controlled by PI3 kinase enzymes in inflammation. The PI3 kinase δ selective inhibitor IC-87114 was found to inhibit airways hyper-responsiveness, IgE release, pro-inflammatory cytokine expression, inflammatory cell accumulation into the lung and vascular permeability in ovalbumin-sensitized, ovalbumin-challenged mice [Lee, K. S. et al., J. Allergy Clin. Immunol., 2006, 118:403-409 and Lee, K. S. et al., FASEB J., 2006, 20:455-65]. In addition, IC-87114 lowered neutrophil accumulation in the lungs of mice and neutrophil function, stimulated by TNFα[Sadhu, C. et al., Biochem. Biophys. Res. Commun., 2003, 308:764-9]. The PI3 kinase δ isoform is activated by insulin and other growth factors, as well as by G-protein coupled protein signalling and inflammatory cytokines. Recently the PI3 kinase dual δ/γ inhibitor TG100-115 was reported to inhibit pulmonary eosinophilia and interleukin-13 as well as mucin accumulation and airways hyperesponsiveness in a murine model, when administered by aerosolisation. The same authors also reported that the compound was able to inhibit pulmonary neutrophilia elicited by either LPS or cigarette smoke [Doukas, J. et al., J Pharmacol. Exp. Ther., 2009, 328:758-765]
Since it is also activated by oxidative stress, the PI3 kinase δ isoform is likely to be relevant as a target for therapeutic intervention in those diseases where a high level of oxidative stress is implicated. Downstream mediators of the PI3 kinase signal transduction pathway include Akt (a serine/threonine protein kinase) and the mammalian target of rapamycin, the enzyme mTOR. Recent work has suggested that activation of PI3 kinase δ, leading to phosphorylation of Akt, is able to induce a state of corticosteroid resistance in otherwise corticosteroid-sensitive cells [To, Y. et al., Am. J. Respir. Crit. Care Med., 2010, 182:897-904]. These observations have led to the hypothesis that this signalling cascade could be one mechanism responsible for the corticosteroid-insensitivity of inflammation observed in the lungs of patients suffering from COPD, as well as those asthmatics who smoke, thereby subjecting their lungs to increased oxidative stress. Indeed, theophylline, a compound used in the treatment of both COPD and asthma, has been suggested to reverse steroid insensitivity through mechanisms involving interaction with pathways controlled by PI3 kinase δ [To, Y. et al., Am. J. Respir. Crit. Care Med., 2010, 182:897-904].
International patent application WO2011/048111 discloses a number of compounds which are inhibitors of PI3 kinases, particularly PI3 kinase δ, including 6-(2-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N,N-bis(2-methoxyethyl)hex-5-ynamide in the free base form which is disclosed therein as Example 83. This compound is also disclosed in WO2012/052753.

The above mentioned compound is referred to herein as “compound of formula (I)” or “compound of formula (I) free base”.
Prior to the applicant′searlier disclosure (WO2011/048111), the PI3 kinase inhibitors described to date have typically been intended for oral administration. However, an undesired consequence of this approach is that non-targeted body tissues, especially the liver and the gut, are likely to be exposed to pharmacologically active concentrations of the drug. An alternative strategy is to design treatment regimens in which the drug is dosed directly to the inflamed organ via topical therapy. In the case of controlling inflammation (or providing another therapeutic effect) in the lungs, this may be achieved by inhalation of the drug, which has the benefit of retaining the drug predominantly in the lungs thereby minimising the risks of systemic toxicity. In order to achieve a sustained duration of action an appropriate formulation which generates a “reservoir” of the active drug may be used.
The compound of formula (I) has, accordingly, been described as being useful for topical administration to the lung (see WO2011/048111).
As well as providing affinity for the target organ and sustained efficacy, a drug for topical administration to the lung via inhalation must also be formulated so as to provide a predictable dose of the drug, which in turn must have predictable and reproducible properties. Achieving acceptable and reproducible chemical and physical stability of the drug in the formulation is a key goal in the product development of pharmaceutical products for all types of pharmaceutical dosage forms. Crystalline forms are preferred, as are forms which are amenable to micronisation.
For inhalation use, there are 3 main dosage forms—a dry powder inhaler (DPI), a metered dose inhaler (MDI) and an aqueous based nebuliser (hand-held or table-top). However the majority of global sales of inhalation products are DPIs and thus provide a well-accepted way of delivering drugs by inhalation. There are numerous commercialized DPI products, such as Flixotide (fluticasone propionate), Advair (fluticasone propionate/salmeterol), Symbicort (budesonide/formoterol), Pulmicort (budesonide), Serevent (salmeterol), Foradil (formoterol).
Dry powder inhalation formulations typically consist of a blend of drug particles (size below 10 microns and normally below 5 microns) with a diluent, typically lactose. Since the usual doses required for inhaled therapies are in the microgram range, the diluent facilitates pharmaceutical processing and dispensing of individual doses e.g. into capsules or blisters or the metering of doses from a bulk reservoir, for subsequent administration to the patient. Therefore, typically, the mass of diluent (the most common being lactose) may be greater than that of the drug substance. In this environment, acceptable formulations of some products can be achieved by simply blending the drug product with lactose. Other products may require other additional excipients or other processing steps in order for the product to meet the requirements of regulatory authorities. For example, U.S. Pat. No. 7,186,401 B2 (Jagotec A G et al.) discloses that the addition of magnesium stearate to dry powder formulations for inhalation improves the moisture resistance of the formulations and allows a high fine particle dosage or fine particle fraction to be maintained under humid conditions. WO00/53157 (Chiesi) describes magnesium stearate as a lubricant to be employed in dry powder formulations for inhalation which is capable if increasing the fine particle dose of certain drugs. US2006/0239932 (Monteith) discloses an inhalable solid pharmaceutical formulation comprising certain active ingredient substances susceptible to chemical interaction with lactose, lactose and magnesium stearate. It is disclosed that magnesium stearate inhibits lactose induced degradation of the active ingredient, presumably via the Maillard reaction which involves the reaction of an amine group on the active ingredient with lactose. US2012/0082727 (Chiesi) discloses a method of inhibiting or reducing chemical degradation of an active ingredient bearing a group susceptible to hydrolysis selected from the group consisting of a carbonate group, a carbamate group and an ester group in a powder formulation for inhalation comprising carrier particles (such as lactose particles) said method comprising coating at least a portion of the surface of said carrier particles with magnesium stearate.
Thus, there remains a need to provide forms of selective PI3 kinase inhibitors for use in inhalation therapy which have the potential to provide therapeutic efficacy in asthma, COPD and other inflammatory diseases of the lungs. In particular, it remains an objective to provide a compound of formula (I) in a crystalline form which has appropriate physical and chemical stability, preferably amenable to micronization, and compatible with pharmaceutical excipients for inhalation therapy, especially lactose.